# New requirements for immunity to parasitic pathogens - when vaccines work and why they fail

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, MERCED · 2021 · $381,079

## Abstract

PROJECT SUMMARY
Immunological memory is the ability of our immune system to respond with greater strength and quickness
upon re-encounter with the same pathogen (i.e. secondary infection). Immunological memory is the basis for
vaccination which remains the most successful method for preventing infectious disease. Yet, a fully protective
vaccine that prevents a single human parasitic disease has not been realized to date. Why is immunity to
parasitic pathogens so difficulty to achieve? Our current work on secondary infections with the
apicomplexan parasite, Toxoplasma gondii, suggest that failure of immunological memory responses is
genetically determined. In this grant submission, we have used a forward genetic approach to uncover new
requirements for host immunity to highly virulent strains T. gondii. Both genetic and immunological data
converge on a B-1b cell population that is specifically expanded in resistant mice. This cell type represents a
bridge between innate and adaptive immune immunity, which can recognize both self- and foreign-
antigen. Our central hypothesis is that memory B-1 cells control resistance to challenge with virulent T.
gondii strains, and this response is determined by allelic variation of Nfkbid. IκBNS, encoded by Nfkbid,
is a member of the atypical nuclear regulators of NF-κB-dependent transcription. Nfkbid null mice fail to
develop B-1 cells and antibody responses to T-independent antigens, and as reported here, have massive
defects in producing T. gondii-specific antibodies. Experimental approaches from immunology, genetics and
molecular parasitology will be used to address questions surrounding our central hypothesis. In Aim 1,
adoptive transfer experiments will be performed to delineate protection conferred by the B-1 lineage and the
functional quality of parasite-specific antibodies they produce. In Aim 2, epigenetic approaches are proposed to
study the mechanism by which IκBNS mediates protective B cell responses during a secondary infection. In
Aim 3, we will explore whether antibody responses directed against GPI-moieties on T. gondii surface antigens
explain parasite strain-differences in secondary infection virulence. Antigenic variation is the major mechanism
by which protozoan pathogens such as African Trypanosomes, Plasmodium sp. and Giardia evade B cell-
mediated antibody responses. Surface antigens of T. gondii are highly polymorphic. Immunity conferred by B-1
cells may depend on their ability to produce antibodies that recognize broadly conserved epitopes within
variable surface antigens. Eliciting this response during vaccination could have major bearing on the
prevention of human parasitic disease.

## Key facts

- **NIH application ID:** 10227131
- **Project number:** 5R01AI137126-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, MERCED
- **Principal Investigator:** Kirk David Christian Jensen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $381,079
- **Award type:** 5
- **Project period:** 2018-09-24 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10227131

## Citation

> US National Institutes of Health, RePORTER application 10227131, New requirements for immunity to parasitic pathogens - when vaccines work and why they fail (5R01AI137126-04). Retrieved via AI Analytics 2026-06-10 from https://api.ai-analytics.org/grant/nih/10227131. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*